Monoclonal antibodies (moAbs) are now an accepted component for non-Hodgkin's lymphoma. Nevertheless, there is still significant uncertainty regarding the relative contributions of the various immune effector mechanisms responsible for the anti-tumor effects of moab. Project #2 was designed to improve our understanding of which effector mechanisms are responsible for anti-tumor effects of moAb therapy and to test the hypothesis that manipulating effector cell function can enhance clinical efficacy. The two specific aims of this proposal are: 1) Evaluate the immune effector mechanisms responsible for the anti- tumor effects of moAb therapy in a murine model of lymphoma and assess how addition of immunomodulatory CpG ODN impacts on various immune effect mechanisms in that model. Determine the role played by various immune effector cells in the anti-tumor activity of moAb. Determine how treatment with CpG ODN impacts on the anti-tumor activity of different effector cells. Evaluate how moAb treatment, with or without CpG ODN, impacts on infiltration into tumor masses of various immune effector cell populations. Evaluate the importance of complement in the anti-tumor activity of moAb 2) Evaluate the effects of clinical therapy with a combination of Rituximab and CpG ODN. Conduct a phase I trial to determine the effect of therapy with CpG ODN and Rituximab on the ability of effector cells to mediate ADCC. Conduct a phase II trial to determine whether ADCC in vitro, mediated by effector cells obtained from subjects treated with CpG ODN plus moAb, correlates with clinical response to therapy. Successful completion of these studies in conjunction with the studies in Project #4, will give us an excellent understand of the role of manipulating effector cell function in the setting of moAb therapy and could have a major impact on the immunotherapy and other malignancies as well.